Outcome in patients with bacterial

meningitis presenting with a minimal

Glasgow Coma Scale score
Marjolein J. Lucas, MD
Matthijs C. Brouwer,
MD, PhD
Arie van der Ende, PhD
Diederik van de Beek,
MD, PhD

Correspondence to
Dr. van de Beek:
d.vandebeek@amc.uva.nl

ABSTRACT

Objective: In bacterial meningitis, a decreased level of consciousness is predictive for unfavorable

outcome, but the clinical features and outcome in patients presenting with a minimal score on the
Glasgow Coma Scale are unknown.

Methods: We assessed the incidence, clinical characteristics, and outcome of patients with bacterial
meningitis presenting with a minimal score on the Glasgow Coma Scale from a nationwide cohort
study of adults with community-acquired bacterial meningitis in the Netherlands from 2006 to 2012.

Results: Thirty of 1,083 patients (3%) presented with a score of 3 on the Glasgow Coma Scale. In
22 of 30 patients (73%), the minimal Glasgow Coma Scale score could be explained by use of
sedative medication or complications resulting from meningitis such as seizures, cerebral edema,
and hydrocephalus. Systemic (86%) and neurologic (47%) complications occurred frequently,
leading to a high proportion of patients with unfavorable outcome (77%). However, 12 of 30 patients (40%) survived and 7 patients (23%) had a good functional outcome, defined as a score of
5 on the Glasgow Outcome Scale. Patients presenting with a minimal Glasgow Coma Scale score
on admission and bilaterally absent pupillary light responses, bilaterally absent corneal reflexes,
or signs of septic shock on admission all died.
Conclusions: Patients with community-acquired bacterial meningitis rarely present with a minimal
score on the Glasgow Coma Scale, but this condition is associated with high rates of morbidity
and mortality. However, 1 out of 5 of these severely ill patients will make a full recovery, stressing
the continued need for aggressive supportive care in these patients. Neurol Neuroimmunol
Neuroinflammation 2014;1:e9; doi: 10.1212/NXI.0000000000000009
GLOSSARY
ICP 5 intracranial pressure.

Bacterial meningitis is a serious and life-threatening disease.1 Streptococcus pneumoniae and

Neisseria meningitidis are the predominant causative pathogens of this disease in adults,2 causing
80%85% of all cases, with high associated morbidity and mortality rates.35 Many patients
with bacterial meningitis present with an abnormal conscious state, and 15%20% of patients
are comatose upon presentation.5 An abnormal conscious state, in most studies graded by the
Glasgow Coma Scale, is a strong predictor for poor disease outcome in bacterial meningitis.5,6
The exact cause of an abnormal conscious state in bacterial meningitis remains unclear, but it is
likely caused by a complex interaction between severe brain inflammation, raised intracranial
pressure (ICP), and resulting complications such as hydrocephalus, cerebral (micro)infarctions,
or epileptic seizures.79 The evaluation of patients with an abnormal conscious state in bacterial
meningitis might further be complicated by the use of antiepileptic or sedative medication.
The clinical features and outcome of the most severely ill patients, those who present with a score
on the Glasgow Coma Scale of 3, are unknown. The time frame for concluding that neurologic
Supplemental data
at Neurology.org/nn
From the Departments of Neurology (M.J.L., M.C.B., D.v.d.B.) and Medical Microbiology (A.v.d.E.) and the Netherlands Reference Laboratory
for Bacterial Meningitis (A.v.d.E.), Academic Medical Center, Center of Infection and Immunity Amsterdam (CINIMA), Amsterdam, the
Netherlands.
Go to Neurology.org/nn for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of
the article. The Article Processing Charge was paid by the authors.
This is an open access article distributed under the terms of the Creative Commons Attribution-Noncommercial No Derivative 3.0 License, which
permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially.
Neurology.org/nn

2014 American Academy of Neurology

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damage is irreversible in these patients is

unclear. In this study we analyzed the incidence,
clinical characteristics, complications, and outcome of patients with bacterial meningitis presenting with a minimal Glasgow Coma Scale
score.
METHODS In a prospective nationwide observational cohort
study in the Netherlands, we included episodes of communityacquired bacterial meningitis confirmed by culture of CSF in
adults. Methods of the MeninGene Study have been described
in detail elsewhere.5,10 In summary, all patients were 16 years of
age or older and were listed in the database of the Netherlands
Reference Laboratory for Bacterial Meningitis from January 2006
to March 2012. This laboratory receives CSF isolates from
approximately 90% of all patients with bacterial meningitis in
the Netherlands. Patients with negative CSF cultures, hospitalacquired meningitis, a neurosurgical device, or who underwent a
neurosurgical operation within 1 month before bacterial meningitis
onset were excluded. Patients using immunosuppressive drugs and
those with asplenia, diabetes mellitus, alcoholism, or infection with
immunodeficiency virus were considered immunocompromised.
Informed consent was obtained from all participating patients or,
in case of decreased consciousness, from their legally authorized
representatives. Clinical data, including specific queries about the
Glasgow Coma Scale score on admission, had been prospectively
collected by means of an online case record form. The Glasgow
Coma Scale grades coma severity according to 3 categories of
responsiveness: eye opening, motor responses, and verbal
responses, with scores ranging from 3 to 15.11 Information
about brainstem reflexes including pupillary light responses,
respiratory drive, EEG data, intubation, and sedative
medication at the time of presentation was not a standard part of
the case record form. These data were all collected retrospectively by
reanalyzing correspondence from ambulance and emergency
departments.

Figure 1

Distribution of scores on Glasgow Coma Scale for adults presenting

with community-acquired bacterial meningitis

At discharge, all patients underwent a neurologic examination

performed by a neurologist, and outcome was graded according
to the Glasgow Outcome Scale. This is a well-validated measurement scale with scores varying from 1 to 5.12 A favorable outcome
was defined as a score of 5 and an unfavorable outcome as a score of
14. Two clinicians independently classified the cause of death.
The interrater agreement (k) for cause of death was 0.73. Differences were resolved by discussion.

Standard protocol approvals, registrations, and patient

consents. The study was approved by the ethics committee of
the Academic Medical Center, Amsterdam, the Netherlands.
RESULTS From 2006 to 2012, 1,083 episodes of
community-acquired bacterial meningitis were
included in the cohort. Thirty of 1,083 patients
(3%) presented with a Glasgow Coma Scale score
of 3 on admission (figure 1). Fifteen patients (50%)
were female and the median age was 65 years
(interquartile range 4976 years; table 1). Fifteen
patients (50%) had one or more predisposing
conditions for bacterial meningitis, consisting of
otitis/sinusitis in 8, immunocompromised state in
6, and pneumonia in 2.
Data on pupillary light responses could be
retrieved for 25 of 30 patients (83%). Pupillary light
responses were bilaterally present in 15 patients
(60%), unilaterally absent in 2 (8%), and bilaterally
absent in 8 (32%; table 1). Anisocoria was noted in
6 of 20 patients (30%). Data on corneal reflexes could
be retrieved for 9 patients, and corneal reflexes were
bilaterally absent in 7 (including 4 patients with bilaterally absent pupillary light responses), unilaterally
absent in 1, and bilaterally present in 1. One patient
had an absent respiratory drive at time of presentation
and died the next day. Of 30 patients, 13 (43%) were
intubated prior to neurologic examination; 5 of these
13 patients (39%) received sedative drugs, 2 of whom
also received muscle relaxant drugs. The remaining
patients did not receive sedative mediation prior to
initial neurologic examination. Eight of 23 patients
(35%) with a minimal Glasgow Coma Scale score presented with neck stiffness, 10 of 30 patients (33%)
presented with seizures, and 9 of 26 patients (34%)
had signs of septic shock at time of presentation.
Seizures consisted of tonic-clonic seizures in all 10 patients; 4 patients received benzodiazepines to stop the
seizures and 1 patient received sedative drugs and muscle
relaxant drugs prior to intubation. One patient had prolonged seizures despite benzodiazepines; it is unknown
how the prolonged seizures were treated in this patient.
Cranial CT on admission was performed in 27 of
30 patients (90%) and was abnormal in 67% (table 1;
figure 2). In 22 of 30 patients (73%), the minimal
Glasgow Coma Scale score could be explained either
by complications resulting from the meningitis (seizures
in 10, hydrocephalus in 5, and cerebral edema in 7) or
by sedative medication (5 patients). In the other 8

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Table 1

Clinical characteristics of 30 patients with bacterial meningitis

presenting with a minimal coma scorea

Characteristics

n/N (%) or median (IQR)

Age, y

65 (4976)

Female

15/30 (50)

Predisposing conditions

15/30 (50)

Otitis/sinusitis

8/30 (27)

Immunocompromised state

6/30 (20)

Pneumonia

2/24 (8)

Duration of symptoms >24 h

14/26 (54)

Symptoms and signs on admission

Bilaterally absent pupillary light reflex

8/25 (32)

Bilaterally absent corneal reflex

7/9 (78)

Temperature 38C

21/29 (70)

Neck stiffness

8/23 (35)

Seizures

10/30 (34)

Systolic blood pressure, mm Hga

130 (120159)

Heart rate, beats/mina

102 (98140)

Signs of septic shock

9/26 (35)

Abnormal cranial CT

18/27 (67)

Generalized edema

8/27 (30)

Hydrocephalus

5/27 (19)

Presumed recent infarction

1/27 (4)

Subdural empyema/effusion

2/27 (7)

Mastoid opacification

7/27 (26)

Sinus opacification

4/27 (15)

Blood chemistry tests

Leukocyte count, cells/mm3

15 (1020)

ESR, mm/h

12 (560)

C-reactive protein, mg/L

221 (110327)

Indexes of inflammation in the CSF

Leukocyte count, cells/mm3

2,240 (16010,750)

Leukocytes <1,000 cells/mm3

10/27 (37)

Protein

5.5 (3.37.2)

CSF: blood glucose ratio

0.01 (00.13)

CSF culture
Streptococcus pneumoniae
Adjunctive dexamethasone

26/30 (87)
25/29 (86)

Abbreviations: ESR 5 erythrocyte sedimentation rate; IQR 5 interquartile range.

a
Systolic blood pressure and heart rate were determined in 27 patients.
b
Defined as diastolic blood pressure ,60 mm Hg, systolic blood pressure #90 mm Hg, or
heart rate $120 beats/min.
c
Leukocyte count was determined in 30 patients, ESR in 9 patients, and C-reactive protein
levels in 30 patients.
d
CSF leukocyte count was determined in 27 patients, CSF protein levels in 28 patients, and
CSF: blood glucose ratio in 29 patients.

patients, the minimal score on the Glasgow Coma Scale

was explained by a direct effect of the meningitis
(defined as a combination of severe brain inflammation
and raised ICP).

Cranial imaging was repeated during admission in

16 patients (all patients underwent CT scan, 1 patient
underwent CT and MRI scan) and was abnormal in
10 patients (63%). New abnormalities not present
on admission were found in 2 patients and consisted
of cerebral infarctions in both.
Twenty-nine of the 30 patients (97%) had at least
one individual CSF finding predictive of bacterial meningitis (glucose level ,34 mg/dL [1.9 mmol/L], ratio
of CSF glucose to blood glucose ,0.23, protein level
.220 mg/dL, or leukocyte count .2,000/mm3).13
Ten of 27 patients (37%) had a CSF leukocyte count
below 1,000 cells/mm3, which has previously been
associated with poor outcome.5 CSF cultures grew S
pneumoniae in 26 patients (87%) and Haemophilus influenzae, Salmonella enterica, Streptococcus pyogenes, and
Staphylococcus aureus in 1 patient each. Initial antibiotic
treatment was microbiologically adequate in all patients
and 25 of 29 patients (86%) received adjunctive dexamethasone on admission.14 The clinical characteristics,
results of cranial imaging, and CSF analysis were similar
when considering only patients who did not receive
sedative medication (table e-1 at Neurology.org/nn).
The majority of patients (87%; table 2) developed
complications during the clinical course. Systemic
complications consisted of respiratory failure (15 of
25 [60%]), pneumonia (6 of 26 [23%]), and hyponatremia (4 of 27 [15%]). Neurologic complications consisted of seizures (7 of 30 [23%]), hearing impairment
(4 of 30 [13%]), cerebral infarction (3 of 30 [10%]),
and subdural empyema (2 of 30 [7%]). EEG was
performed in 5 patients during the clinical course. Four
of these patients had an isoelectric EEG (1 to 3 days
after admission) and treatment was withdrawn resulting in immediate death. In 1 patient, the EEG was
performed on the eleventh day showing severe cortical
dysfunction (with some residual cerebral activity). Care
was withdrawn and the patient subsequently died of
multiorgan failure. One patient with hydrocephalus
was treated with external ventricular drainage on the
day of admission but died 3 days later. Four patients
with hydrocephalus were not treated with external ventricular drainage because of other poor prognostic factors (multiorgan failure, clinically brain dead) or
because the hydrocephalus was mild and spontaneously resolved on follow-up imaging. None of the patients were treated with continuous ICP measuring
and ICP-directed treatment.
Twelve of the 30 patients (40%) survived and 7 patients (23%) had a good functional outcome, defined as
a score of 5 on the Glasgow Outcome Scale. Neurologic sequelae were present on discharge in 5 of 12 survivors (42%) and consisted of cognitive impairment in
4, poor general condition in 2, and bilateral hearing loss
and hemiparesis in 1 patient each; 3 surviving patients
with sequelae were scored as moderately disabled on

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Figure 2

Spectrum of abnormal CT scanning of patients with bacterial

meningitis presenting with a minimal Glasgow Coma Scale score

Table 2

Complications and outcome of 30

patients with bacterial meningitis
presenting with a minimal coma score
n/N (%) or
median (range)

Characteristic
Systemic complications
Respiratory failure

15/25 (60)

Pneumonia

6/26 (23)

Hyponatremia

4/27 (15)

Neurologic complications
Cerebral infarction

3/30 (10)

Subdural empyema

2/30 (7)

Hearing impairment

4/30 (13)

Seizures

7/30 (23)

Outcome
GOS 1

18/30 (60)

GOS 2

GOS 3

2/30 (7)

GOS 4

3/30 (10)

GOS 5
Time to death, d

7/30 (23)
a

2 (122)

Causes of death

(A) Generalized cerebral edema with signs of pseudo-subarachnoid hemorrhage; (B) subdural empyema; (C) generalized cerebral edema indicating severe cerebral inflammation;
(D) hydrocephalus.

the Glasgow Outcome Scale and 2 as severely disabled requiring nursing home admission. All 11 patients presenting with either bilaterally absent
pupillary light responses or bilaterally absent corneal
reflexes died (table 3). Furthermore, all 9 patients with
signs of septic shock on admission died; septic shock
was defined as diastolic blood pressure ,60 mm Hg,
systolic blood pressure #90 mm Hg, or heart rate
$120 beats per minute. The mortality rate and frequency of sequelae were similar when considering only
patients who did not receive sedative medication on
admission (table e-2).
The causes of death in the 18 deceased patients
were as follows: extensive neurologic damage due
to meningitis (6 patients), acute brain herniation
shown on cranial imaging (4 patients), withdrawal
of care because of poor neurologic prognosis (2 patients; care was withdrawn 2 and 3 days after
admission), multiorgan failure or septic shock (2
patients each), and cardiac arrest or delayed cerebral thrombosis (1 patient each).15 Autopsy was
performed in 3 patients showing severe brain damage in all patients. In 1 patient venous sinus
thrombosis was identified that was not diagnosed
prior to autopsy.
4

Extensive neurologic damage

due to meningitis

6/18 (33)

Withdrawal of treatment

2/18 (11)

Brain herniation on CT

4/18 (22)

Multiorgan failure

2/18 (11)

Septic shock

2/18 (11)

Cardiac arrest

1/18 (6)

Delayed cerebral thrombosis

1/18 (6)

Neurologic sequelae

5/12 (42)

Cognitive impairment

Poor general condition

Bilateral hearing loss

Hemiparesis

Abbreviation: GOS 5 Glasgow Outcome Scale.

a
Data concerning 18 deceased patients.

DISCUSSION Our study shows that a small minority

of patients with community-acquired bacterial
meningitis presents with a minimal score on the
Glasgow Coma Scale (3%). Although the majority of
these patients had an unfavorable outcome (77%)
and many patients died (60%), the number of
patients who recovered completely was substantial.
We could not identify clinical parameters predictive for
favorable outcome, for example epileptic seizures or
sedative drugs. However, patients presenting with
a minimal Glasgow Coma Scale score on admission
and bilaterally absent pupillary light responses,
bilaterally absent corneal reflexes, or signs of septic

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Table 3

Clinical characteristics of patients with bacterial meningitis presenting

with a minimal coma score with good outcome and with poor outcome
Favorable
outcomea (n 5 10)

Unfavorable
outcomeb (n 5 20)

Seizures

3/10 (30)

7/20 (35)

Sedation

2/10 (20)

3/20 (15)

Characteristic
Symptoms and signs on admission

Septic shock

0/6

9/20 (45)

5/9 (56)

13/18 (72)

Generalized edema

2/9 (22)

6/18 (33)

Hydrocephalus

1/9 (11)

4/18 (22)

Leukocytes <1,000 cells/mm3

1/10 (10)

9/17 (53)

Protein, median (IQR)

5.5 (2.77.1)

5.4 (3.98.2)

9/10 (90)

17/20 (85)

10/10 (100)

15/19 (79)

Abnormal cranial CT

Indexes of inflammation in the CSFc

CSF culture
Streptococcus pneumoniae
Adjunctive dexamethasone

Abbreviations: GOS 5 Glasgow Outcome Scale; IQR 5 interquartile range.

Data are n/N (%). unless otherwise specified.
a
Favorable outcome is defined as GOS 45.
b
Unfavorable outcome is defined as GOS 13.
c
CSF leukocyte count was determined in 27 patients and CSF protein level in 28 patients.

shock on admission all died. Physicians confronted with

a patient with bacterial meningitis presenting with
a minimal Glasgow Coma Scale score should be aware
that at least 1 out of 5 patients will make a full recovery.
Neuroimaging showed that 1 out of 4 patients with
bacterial meningitis presenting with a minimal score on
the Glasgow Coma Scale have cerebral abnormalities
such as hydrocephalus or subdural empyema, which
may require emergency neurosurgery. Hydrocephalus
and empyema rarely complicate bacterial meningitis
(3%5% of patients) but have been associated with
high rates of death and unfavorable outcome.1618 Early
identification and subsequent neurosurgical treatment
of these complications may improve prognosis. Therefore, immediate cranial imaging should be a priority in
patients with a minimal score on the Glasgow Coma
Scale on admission to rule out treatable conditions.
Because of the risk of increasing brain shift due to lumbar puncture, cranial imaging should precede lumbar
puncture in all patients with a minimal Glasgow Coma
Scale score to rule out space-occupying lesions causing
brain shift.8 Antibiotic therapy and adjunctive dexamethasone therapy if indicated should be started before
sending the patient to the imaging room. Although
some authors have advocated the use of continuous
ICP measuring and ICP lowering by use of CSF drainage and medication, the benefit of ICP management in
these patients is still unclear.19,20
The abnormal conscious state could be explained
by potentially reversible causes, such as seizures, sedative medication, or muscle relaxants, in a subgroup

of patients (47%). However, these patients had similar

outcomes compared to the other patients, suggesting
that seizures and the need for intubation are markers
of disease severity rather than indicators of a reversible
cause of an abnormal conscious state. A minimal score
on the Glasgow Coma Scale was preceded by epileptic
seizures in 33% of patients and 5 patients received
antiepileptic or sedative medication as treatment for
seizures. Epilepsy has previously been described in
17% of patients with bacterial meningitis.21 If no clear
explanation for a minimal coma score other than severe
inflammation can be found, an EEG should be performed. This is also true for those patients with a waxing and waning level of consciousness. In 9 patients,
signs of septic shock were present on admission and
likely contributed to the minimal Glasgow Coma Scale
score. Three of them also had seizures and one received
sedative medication; in the other 5 patients, there was
no explanation for the minimal coma score other than
septic shock. Stabilization of hemodynamics is of the
utmost importance early during sepsis and should have
priority in patients with meningitis with concomitant
sepsis. Despite aggressive management of the patients
with sepsis included in our study, all patients with signs
of septic shock on admission eventually died.
This study has several limitations. First, several clinical characteristics of patients with a minimal Glasgow
Coma Scale score on admission were not routinely captured in the case record form (for example, brainstem
reflexes, anisocoria, sedative medication), but these
data were collected retrospectively. Furthermore, patients with a minimal score on the Glasgow Coma
Scale may have been missed: patients with bacterial
meningitis presenting with a minimal coma score
may have severe brain edema, prohibiting a lumbar
puncture. Another reason to withhold a lumbar puncture may be diffuse intravascular coagulation, which
may occur due to concomitant sepsis. In patients with
meningitis with predominant signs of septic shock,
meningitis may be missed because the typical sign of
meningitis, neck stiffness, is often absent in comatose
patients. All these factors may have lead to an underestimation of the incidence of a minimal Glasgow Coma
Scale score in patients with bacterial meningitis. Furthermore, this is an observational study, and all treatment decisions (for instance to place CSF catheters,
operate for subdural empyema, or use ICP management) were at the discretion of the treating physician.
Therefore, treatments between patients were different,
which is likely to have influenced outcome. This implies our study cannot be used to determine treatment
effects, but it does reflect clinical practice as it currently
is in the Netherlands. Finally, only patients with positive CSF cultures were included. Negative CSF cultures
are estimated to occur in 11%20% of patients with
bacterial meningitis.2224 However, the clinical

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presentation of patients with culture-positive bacterial

meningitis and patients with culture-negative bacterial
meningitis was reported to be similar.
Patients with community-acquired bacterial meningitis rarely present with a minimal score on the
Glasgow Coma Scale, but this condition is associated
with high rates of morbidity and mortality. However,
1 out of 5 of these severely ill patients will make a full
recovery, stressing the continued need for aggressive
supportive care.
AUTHOR CONTRIBUTIONS
Marjolein Lucas performed the data analysis and wrote the manuscript.
Matthijs Brouwer performed the data analysis and wrote the manuscript.
Arie van der Ende wrote the manuscript. Diederik van de Beek performed the data analysis, wrote the manuscript, is the principal investigator of the study, and provided funding.

ACKNOWLEDGMENT
We are indebted to all Dutch physicians who participated in the study. We
acknowledge research funding for the MeninGene study (Netherlands
Organization for Health Research and Development, the Academic Medical Center, and the European Research Council).

6.

7.

8.

9.

10.
11.
12.

13.

14.

STUDY FUNDING
This research has been supported by grants from the Netherlands Organization for Health Research and Development (Veni [916.76.023] and
Vidi [016.116.358] to D.v.d.B.; Veni [916.13.078] to M.C.B.), the Academic Medical Center (AMC Fellowship 2008 to D.v.d.B.), and the
European Research Council (ERC Starting Grant to D.v.d.B.).

15.

16.

DISCLOSURE
M.J. Lucas and A. van der Ende report no disclosures relevant to the
manuscript. M.C. Brouwer has received research support from the Dutch
Scientific Organization, The European Federation of Neurological Sciences, and the European Society of Clinical Microbiology and Infectious
Diseases. D. van de Beek is an editor for BMC Infectious Diseases and
Cochrane Acute Respiratory Infections Group and has received research
support from Omeros, The Academic Medical Center, and the European
Research Council. Go to Neurology.org/nn for full disclosures.

17.

18.

19.

Received February 10, 2014. Accepted in final form April 3, 2014.

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